International Journal of Nanomedicine
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Open Access Full Text Article
The Influence of Nanoparticle Properties on Oral
Bioavailability of Drugs
International Journal of Nanomedicine downloaded from https://www.dovepress.com/ on 21-Oct-2023
Yuanyuan Wang*
Chao Pi*
Xianhu Feng
Yi Hou
Ling Zhao
Yumeng Wei
For personal use only.
Central Nervous System Drug Key
Laboratory of Sichuan Province, School
of Pharmacy, Southwest Medical
University, Luzhou, Sichuan 646000,
People’s Republic of China
*These authors contributed equally to
this work
Correspondence: Ling Zhao; Yumeng Wei
Tel/Fax +86 830 3162292;
+86 830 3162291
Email zhaoling-998@163.com;
weiyumeng-268@163.com
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http://doi.org/10.2147/IJN.S257269
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This article was published in the following Dove Press journal:
International Journal of Nanomedicine
Abstract: Oral administration has been the most common therapeutic regimen in various
diseases because of its high safety, convenience, lower costs, and high compliance of patients.
However, susceptible in hostile gastrointestinal (GI) environment, many drugs show poor
permeability across GI tract mucus and intestinal epithelium with poor oral absorption and
limited therapeutic efficacy. In recent years, nanoparticulate drug delivery systems (NDDS) have
become a hot research spot because of their unique advantages including protecting drug from
premature degrading and interacting with the physiological environment, increasing intracellular
penetration, and enhancing drug absorption. However, a slight change in physicochemistry of
nanoparticles can significantly impact their interaction with biological pathways and alter the
oral bioavailability of drugs. Hence, this review focuses on the factors affecting oral bioavail­
ability from two aspects. On the one hand, the factors are the biochemical and physiological
barriers in oral drugs delivery. On the other hand, the factors are the nanoparticle properties
including size, surface properties, and shape of nanoparticles.
Keywords: oral bioavailability, nanoparticle properties, size, shape, surface properties
Introduction
Oral administration has been the most common manner of drug delivery for thousands
of years, with some advantages including the safety, it being well-tolerated, with low
treatment costs, good compliance, and convenience.1,2 Despite its outstanding advan­
tages, the traditionally oral administered drugs are faced with the daunting challenges
of poor and highly variable bioavailability, which can be frequently caused by inherent
instability and low solubility in variable conditions of the gastrointestinal (GI) tract,
poor permeability through GI barriers, and, in some cases, extensive pre-systemic
metabolism in the GI tract and liver (eg, cytochrome P-450).2,5
To surmount these barriers in the GI tract and significantly improve oral bioavail­
ability, designing and developing some effective oral drug delivery systems is quite
urgent.6 Thus, a large variety of new techniques and dosages of drugs have been
developed such as protein or polymer conjugates,7 solid drug dispersions,8 nanoparticle
technologies,9 and macroscopic systems such as capsules, gels, and films.10 Among
these strategies, nanoparticulate drug delivery systems (NDDS) have been attracting
more attention since they can protect the drug from premature degradation and inter­
action with the physiological environment, increase intracellular penetration, and
enhance drug absorption (Figure 1).11,14 By far, numerous NDDS including albumin
nanoparticles,15 chitosan (CS) nanoparticles,16 liposomes,17 polymeric micelles,18 etc.
have been developed for the oral delivery of different drugs.
International Journal of Nanomedicine 2020:15 6295–6310 6295
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Figure 1 The benefits of using nanoparticles.

Abbreviation: GI, gastrointestinal.

However, previous studies have reported that a slight
change in physicochemistry of nanoparticles can significantly
impact on their interaction with biological pathways and alter
the oral bioavailability of drugs.6,11,19 For example, the control
of dimension under 200 nm was more absorbed by the GI
tract.4,20,21 And other reports found that polystyrene (PS)
nanoparticles decorated with vitamin B12 (VitB12) were more
easily avoiding lysosomal digestion as well as entering epithe­
lial cells, compared with both soluble VitB12 ligand and
unmodified nanoparticles.22 In addition to the influence of
size and surface properties of nanoparticles, another paper
reported that oral bioavailability of drugs was also signifi­
cantly impacted by nanoparticle geometry,23–25 such as the
fact that rod-nanoparticles had better oral bioavailability com­
pared with sphere-nanoparticles.26 Therefore, it is necessary to
summarize the role of the size, surface properties, and shape of
nanoparticle in oral drug delivery. We believe that understand­
ing the role of nanoparticle properties in GI tract transport as
well as cellular uptake can bring forth a paradigm shift in
nanoparticle engineering for oral delivery. Hence, this review
focuses on the factors affecting oral bioavailability, in which
these factors are divided into two categories: the biochemical
and physiological barriers in oral drugs delivery; and the
nanoparticle properties including size, surface properties, and
shape of nanoparticles (Figure 2).
Physiological and Biochemical
Disorders in Oral Delivery
Although oral drug delivery has been widely used in
clinical practice, oral bioavailability has always been lim­
ited by the disorders of oral administration, including the
variation in PH conditions, surfactants, and rich enzyme
content in the GI tract, loose and firm mucus, and trans­
porters in vivo. Thus, it is vital to give an insight into the
obstacles for the development of oral drugs and the boost­
ing of oral bioavailability of drugs.27
Biochemical Barriers
After oral administration, drugs would confront a harsh bio­
chemical environment,28 which comprises of PH variation in
the GI tract, metabolizing enzymes, surfactants like bile salt,
and the liver itself.4 The drugs can be destroyed by acidic
environment, especially materials that are sensitive to acidic
conditions.28 Furthermore, the variation in PH conditions is
from acidic to alkaline along the GI tract, which imposes
a hurdle to the stability of drugs and sometimes their
carriers.29 In addition, surfactants in the GI tract also have
a substantial impact on the structural integrity of drugs.29
Beyond these, the drugs after oral administration still have to
face a particularly rich enzyme content, composed of pro­
teases, lipases, or amylases.30 These enzymes exist in the
digestive tract, especially in the lower one, which are respon­
sible for the metabolism.4 After entering intestinal epithelial
cells, the drugs will be threatened by extra-hepatic micro­
somal enzymes on the endoplasmic reticulum inside the
cytoplasm liver (eg, the cytochrome P450 3A family of
phaseⅠ metabolic enzymes).31 In conclusion, the bioavail­
ability of drugs can be limited by the biochemical barriers
after oral administration. Hence, the numerous drugs are
encapsulated to nanoparticles. Furthermore, the materials
used as the nanocarrier should be carefully chosen or chemi­
cally modified adequately.28

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Figure 2 (A) The nanoparticle properties including size, surface properties, and shape of nanoparticles. (B) Schematic representation illustrating the biochemical and
physiological barriers of oral drug delivery. (C) The relationship of the nanoparticle properties, oral bioavailability, and barriers in oral delivery.
Physiological Barriers
Mucus Barriers
Some reports mentioned that drugs must be capable of pene­
trating and crossing mucus barriers in order to be absorbed
and gain access to the circulatory system and target
tissue.32,33 The mucus layer is ubiquitous in the GI tract
composed of water, proteins, lipids, electrolytes, antimicro­
bial peptides, sloughed epithelial cells, bile salts, and other
components available in the GI tract.34,35 Mucus can be
divided into two types: loose and firm mucus (Figure
3B).36 Loose mucus is easy to be removed by suction as
well as shear and high thickness of the layer.37,38 However,
firm mucus adheres firmly or anchors to the epithelium sur­
face and is resistant to the removal by suction and shear.37
The main structural constituent of the mucus layer is mucin
(Figure 3A) that can be defined as glycoproteins containing
heavily O-glycosylated serine/threonine-rich tandem repeat
domains.33,39 The oligosaccharide side chains including
a terminal carboxyl group or ester sulfate groups give
mucus its negative charge.33,40,41 Some positively charged
drugs and their carriers have been shown to have electrostatic
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Wang et al
interactions with the glycoproteins from mucus, limiting the
drugs absorption rate and decreasing the oral bioavailability
of drugs.34 Meanwhile, hydrophobic bare globular regions
(non-glycosylated regions) with high density located on
mucin chains generate multiple low-affinity adhesion inter­
actions with hydrophobic regions of foreign particles.42 The
large number of hydrophobic drugs through the mucus can be
rapidly removed, impairing drug effective therapy.42 In addi­
tion, mucin molecules can form a network via disulfide
bonds. The non-glycosylated regions of the mucin molecule
are the site of interchain disulfide bridge that connects the
glycoprotein subunits.43 The mesh space and the brush-like
structure of mucus can act as a size exclusion filter, reducing
the mobility of large molecules, thereby increasing their
clearance rate.40,44,46 Another intriguing finding is that the
thickness of the mucosal barrier varies with the location of
the GI region (Table 1).35,36 Crossing the mucus layer implies
a particle size below 200 nm.28 Indeed, nanocarriers should
be small enough to avoid being blocked by the mucin mesh.
Moreover, interactions between the surface of nanocarriers
and mucus must be kept at a minimum.
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Figure 3 (A) Highly O-glycosylated mucin domains. Red, protein core; Green, oligosaccharides. (B) Schematic representation illustrating two types of mucus.
Abbreviations: Ser, serine; Thr, threonine; Pro, proline; Cys, cysteine; S-S, disulfide bonds; Ser-O-GalNAC, O-glycosylated serine.

Absorption Barriers of the Intestinal Epithelium patches.47,50 The transcellular pathway mainly absorbs par­
Intestinal epithelium with dense and orderly brush border on ticles through the cell membrane of enterocytes relying on
the top surface is an intrinsic physical barrier that consists of their size and hydrophobicity.50 In the absence of aggrega­
a single layer of columnar epithelial cells comprised of tion, the particles of smaller size are more easily absorbed by
absorptive (enterocytes) and secretory cells (goblet cells intestinal epithelial cells. It has been reported that a particle
and paneth cells).47,49 Epithelium permeation of drugs can size smaller than 300 nm could be untaken by enterocytes,
occur via transcellular route, paracellular avenues, and the while a size larger than 500 nm was more likely to be
densely clustered M cells located on the surface of Payer’s absorbed in jejuna Payer’s patches.50,52 The paracellular
pathway is another limiting step in transepithelial transport,
mediated through tight junctions (TJs), which is the way for
Table 1 Thickness of Mucus in Different Parts of the Human
the hydrophilic molecules uptake.49,50,53 Moreover, most
Gastrointestinal Tract
macromolecular drugs do not readily enter systemic circula­
Mucus Membrane Total Mucus Thickness (μm) Ref
tion through intercellular connections. It is reported that Ca2+
Gastric 30–300 [37] chelating agents could increase the paracellular permeability
Small Intestine 150–400 [37] by reversible opening of the tight junctions.54,55 Payer’s
Ileum 400–500 [36]
patches are actually the submucosal mass lymph node of
Colon 30–700 [36,37]
the small intestine, which are the main site of intestinal

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mucosal immune induction. M cells located on the surface of
Payer’s patches act as an entrance for drugs to the lymphatic
vessels, especially lipid soluble drugs, from the intestinal
cavity to lymphoid cells, which shall reduce the primary
clearance of the liver.50 However, the lymphatic pathway
shows only a high affinity for lipophilic compounds.
Ling et al56 increased the bioavailability of cefotaxime via
liposome preparation compared with aqueous solution and
the physical mixture.
Transporters in vivo
In addition, there are a variety of transporters in vivo, such as
P-glycoprotein (P-gp), cytoplasmic transporter, breast cancer
drug resistant proteins, and multidrug resistance associated
protein, which release drugs from the intracellular environ­
ment to outside of the cell.4 P-gp encoded by multidrug
resistance-1 gene is the major drug efflux transporter
system.4 A lot of drugs (eg, paclitaxel (PTX), docetaxel,
etoposide, vinblastine, vincristine, and doxorubicin) are
known as potential substrates of efflux transporters. Various
efflux transporters in vivo infinitely restrict oral absorption of
drugs.4 Therefore, active modification of drug carriers is
essential.
The Effect of Size for Oral
Bioavailability
It has been reported that the bioadhesion of solid lipid
nanoparticles (SLNs) in the GI tract can be improved via
smaller size to prolong their residence time and thus play
a contributing role in improving oral bioavailability.4,57,58
Retinoic acid-SLNs showed an increase of 3-fold oral
bioavailability of retinoic acid when particle size decreases
from 328.8 nm to 89.3 nm.59 The fact proved that particle
size plays a crucial role in oral drug delivery.60
It has been concluded previously that particle size has
a great impact on the movement of particles in the mucus.
For instance, Maisel et al61 found that particles of 40 and
100 nm in size spread over the mucosa reaching to the
deep, folded surfaces of the colorectal epithelium, whereas
particles 200 and 500 nm in size just spread over the
surface. The data indicate that particles with smaller size
are easily reaching to the firm mucus that is resistant to the
removal by suction and shear, thereby prolonging their
residence time. In addition, the cellular uptake and uptake
pathway of particles are also affected by the size of nano­
particles. The smaller nanostructured lipid carriers (NLC-
100 nm) show higher uptake efficiency in the Caco-2 cell
(P<0.05) as well as higher permeation ability in Caco-2
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cell monolayer (P<0.01) compared with NLC-200 nm and
NLC-300 nm.62 Moreover, pharmacokinetic studies shown
that NLC-100 nm exhibited highest Cmax and AUC com­
pared with the others.62 Zhao et al63 also mentioned that
the 100 nm nanovaccine exhibited better pharmacokinetic
efficacy than the 500 nm nanovaccine in the presence of
alum adjuvant. Li et al62 concluded from their data that the
size of 100 nm might be the most suitable size for oral
delivery of nanoparticles. However, the data of Banerjee
et al6 indicated that particle uptake by Caco-2 and Caco-2/
HT-29 cells was inversely related to their size, with uptake
of 50 nm > 200 nm > 500 nm > 1000 nm.6 Thus, the
hypothesis can be mentioned that nanoparticle size has
a negative correlation influence on oral bioavailability of
drugs during the certain range. However, the optimal par­
ticle size still needs to be actively explored by researchers
in oral drug delivery.
The Effects of Surface Properties for
Oral Bioavailability
NDDS have many desirable characteristics for drug admin­
istration such as improving solubility and stability of
drugs.64 However, even the most potent extended release
nanoparticle would be rapidly cleared from the body if it
adheres to the superficial layers of mucus, reducing delivery
of the drug to the target tissues.65 The report demonstrated
that the surface chemistry of nanoparticles can greatly
impact their interaction with biological pathways and alter
efficacy (Table 2).11 Efficient oral delivery of drugs based
on NDDS requires simultaneously overcoming physiologi­
cal and biochemical disorders of the body, which needs very
different or even contradictory surface properties of
nanocarriers.66 In general, it is a necessity to achieve
a variety of treatment goals with different materials or
different modifications to nanoparticles. Thus, definitely
learning the role of surface properties of nanoparticles
about oral delivery is important.
The Particle Containing a Hydrophilic
Group
As previously discussed, after entering the GI tract
through the esophagus, the oral drugs can be removed by
non-covalent bonds (such as hydrophobic bonds, hydrogen
bonds, and electrostatic forces) with GI mucus, especially
the superficial GI mucus, to prevent it entering the sys­
temic circulation, thereby reducing the effective dosage of
drugs. Neutral hydrophilic materials (Figure 4) get more
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Table 2 The Effect of Various Surface Modification Materials of doxorubicin (DOX) loaded PLGA-Nanoparticles
Nanoparticles on the Oral Administration (PEGylated-DOX-PLGA-NPs) observed a 6.8-fold oral
Material Influential Effect Ref bioavailability as compared to DOX-S in pharmacokinetics
studies.68 In addition, Feeney et al69 modified lipid nanopar­
PEG Increasing mucus penetration (~5 KDa) [62]
ticles (LN) by using carrier materials of hydrogenated castor
Reduce recognition and clearance [37,71]
oil (HCO) and castor oil (CO) (containing PEG groups).
Enhance plasma circulation times [71] They found that the relative bioavailability (defined as the
Promote drug accumulation [37]
ratio of AUC 0–∞ for the modified LN and its structurally
analogous LN) of the formulations was 120% and 182% for
TA Improve solubility of hydrophobic [75]
HCO and CO formulations, respectively. However, some
molecules
articles also mentioned PEG had a strong viscosity, which
Inhibitory effect of P-gp [81] speculated hydrogen bonding between ether oxygen atoms in
Avoid gastric acid degradation [2] PEG and sugars on glycosylated mucins. Wang et al70
explored the physicochemical properties of PEG-coated
Polycation Increase solubility of hydrophobic [84]
molecules
nanoparticles, specifically PEG molecular weight and degree
of surface coverage, to reconcile the paradoxical reports of
PECs Facilitating mucus transport [43,85]
PEGs interactions with mucus. They explored the physico­
Increasing cellular penetration [89] chemical properties of PEG-coated nanoparticles which were
Lipid material Increase the lymphatic absorption [84]
formulated from PS modified PEGs of various molecular
(log P>5) Prevent the liver from first pass weights (2, 5, 10 kDa) to reconcile the paradoxical reports
metabolizing of PEGs interactions with mucus. They found that PS-
[84]
PEG2K(High) nanoparticles penetrated mucus with effective
speed only 7-fold reduced compared with in water. And they
Specific Increasing cellular uptake [96]
concluded that low molecular weight and high (dense) PEG
ligands
surface coverage was required for rapid mucus penetration of
Abbreviations: PEG, ploy(ethylene glycol); TA, tannic acid; PECs; polyelectrolyte
complexes; P-gp, P-glycoprotein.
coated particles, and that dense PEG coatings transferred
from being mucoinert to mucoadhesive when a critical mole­
cular weight existed between 5 and 10 kDa.
and more attention because of their difficulty in hydropho­
bic and electrostatic interaction with GI mucus. Such sub­
Coating Particles with Tannic Acid (TA)
stances that are easy to penetrate the mucus barrier are TA is a type of the natural polyphenols which is constituted
called mucopenetrating particles (MPP), which can plentiful catechol and pyrogallol moieties and generally recog­
improve epithelial distribution and retention time by pene­ nized as safe by the United States Food and Drug
trating the outer, rapidly clear mucus layers to reach the Administration (FDA).71,72 In recent years, it has been reported
more slowly cleared layers and increase the effective that TA can improve solubility of hydrophobic molecules by
amount of drugs into the systemic circulation.67 hydrogen bonding.73 Shen et al72 proved that TA anchored
onto the surface of hydrophobic PTX nanocore via multiple
PEGylated Drug Delivery Vehicles hydrogen bonding between pyrogallol or catechol groups of
The poly(ethylene glycol) (PEG), a passive mucopenetrating TA and hydroxyl groups or oxygen atoms of PTX molecules.
system, has been widely used in surface modification of The X-ray diffraction (XRD) pattern of the pure PTX powder
nanoparticles due to the property of reducing interactions showed a number of sharp Bragg peaks, corresponding to
with both luminal components and mucus in the gut.36 highly crystalline PTX.74 No discernible peaks appeared for
Maisel et al61 used PEG-modified poly(lactic-co-glycolic the TA-PTX complex, indicating the amorphous nature of the
acid) (PLGA) nanoparticles to study the mucus-penetrating complex coating.72 The data of release kinetics indicated that
of particles under different conditions (eg, providing normal TA-PTX complex nanoparticles displayed a gradual release
and colitis mice model, or increasing the volume of gavage), profile without burst release at an initial stage and finally
and concluded that the particles were uniformly distributed reached 90% of drug release after 36 hours.72 The good dis­
on the mucosa of epithelial cells. In the PEGylated solution behavior can be attributed to their amorphous nature

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Figure 4 Structural formula of partial materials containing hydrophilic groups.
of PTX in the complex nanoparticles, which was helpful to
improve bioavailability.75 In addition, TA has been verified to
exhibit high biological activities,76,77 such as inhibited effect of
P-gp. It is all known that P-gp-mediated efflux is one of the
major absorptive barriers in vivo.78 Kitagawa et al79 demon­
strated that TA displayed the P-gp inhibitory function by
ATPase inhibition. Some scholars believed that nanoparticles
conjugated TA can avoid gastric acid degradation, achieve PH
dependent intestinal site release, and increase oral absorption
of drugs.2 They rationally developed a hydrogen-bonded TA
acid-based nanoparticle, TA-PTX nanoparticles, via a flash
nanoprecipitation process, and explored PH-sensitive beha­
viors of TA-PTX nanoparticles at different pH conditions.
They found that the TA-PTX nanoparticles solution exhibited
strong opaque property at acidic conditions and then recovered
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to 85% optical transmittance after adjusting to pH 7.4. The
particles’ diameter immediately increased from 54 nm to about
2 µm after dispersing in pH 2, while reduced to 70 nm in pH
7.4. In addition, it was worth mentioning that microaggregates
can be found in pH 2, and the approximate recovery of particle
size to original state of TA-PTX nanoparticles when pH was
adjusted to 6.8 or 7.4. These results suggested that TA-PTX
nanoparticles can reduce the burst release of drugs, possibly
prevent the acidic degradation of PTX in the stomach, and
achieve intestinal site-specific drug release through physiolo­
gical pH stimulation.
Coating Particles with Other Hydrophilic Substance
A great number of other hydrophilic substances are
abounding in nature, such as polyethylene oxide (PEO),
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 Wang et al
poloxamer 188, and pluronic F-127 (PF-127). To enhance
mucus permeation and promote cellular uptake compared
with cabazitaxel (CTX), Ren et al80 formulated CTX poly­
mer–lipid hybrid nanoparticles (CTX-PMONP). The nano­
carriers were comprised of a poly(ε-caprolactone) (PCL)
and chain triglyceride hybrid core for drug loading, and
encased in PEO shell by insertion of poloxamer 188.80 The
oral bioavailability of CTX was elevated from 7.7% CTX
solution (CTX-Sol) to 56.6% after oral administration of
CTX-PMONPs, approximately 7.3-times higher than that
of CTX-Sol.80 In addition, Li et al81 found that when the
mucoinert polymer PF-127 was incorporated, the mucus
penetrating properties of liposomes were improved signif­
icantly. PF127-inlaid liposomes and PF127-adsorbed lipo­
somes were prepared by a thin-film hydration method
followed by extrusion, in which coumarin 6 was loaded
as a fluorescence marker.81 A modified Franz diffusion cell
mounted with the intestinal mucus of rats was used to
study the diffusion characteristics of the two types of
PF127 liposomes.81 The diffusion efficiency of the two
types of PF127-modified liposomes through intestinal rat
mucus was 5-7-fold higher than that of unmodified lipo­
somes. In general, hydrophilic materials are easy to pene­
trate the mucus barrier because of their difficulty in
hydrophobic and electrostatic interaction with GI mucus,
thereby increasing the effective amount of drugs into the
systemic circulation.
The Particle Containing Polycationic
Group
Formulation drugs with polycationic and surface-modified
polycation particles have been shown to increase solubi­
lity, protect labile compounds from pH changes, and diges­
tive enzymes.82 And some studies also illustrated that
apart from uncharged nanoparticles with hydrophilic and
a low hydrogen bonding capability, a densely charged
nanoparticle yet net neutral surface can be also considered
as MPP. These particles with neutral surface, high surface
charge density of polyelectrolyte complexes (PECs), can
create a hydrophilic surface that decreases its hydrophobic
interactions with mucus and facilitate mucus transport.42,83
CS, an attractive polymer, has been extensively used in
oral delivery. The combination of CS and chondroitin
sulfate was used to prepare PECs that could penetrate
mucus to the higher extent compared with reference
nanoparticles.84 In addition, interferon alpha (IFNα)-
loaded CS-nanoparticles were prepared by the ionotropic
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gelation method between the polycationic CS and sodium
tripolyphosphate pentabasic anions, which were a potential
delivery system for the oral administration compared with
IFNα.85 Dyawanapelly et al86 developed PLGA nanopar­
ticles, surface-modified chitosan oligosaccharide (COS)-
PLGA nanoparticles, and CS-PLGA nanoparticles and
compared mucoadhesion of CS and COS surface-
modified polymer nanoparticles for mucosal delivery of
proteins. Their data indicated that positively charged COS-
PLGA nanoparticles and CS-PLGA nanoparticles exhib­
ited higher mucoadhesion than negatively charged PLGA
nanoparticles. Wang et al87 also prepared PLGA nanopar­
ticle coating with CS and performed cellular uptake
mechanisms as well as transmembrane permeability in
Madin-Darby canine kidney-cell monolayers. They found
that, under all conditions, CS-PLGA nanoparticles showed
a greater potential to be transported into cells.
Furthermore, pharmacokinetic studies demonstrated
marked improvement of 3.53-fold and 8.03-fold in
Wistar rat’s plasma as well as brain higher oral bioavail­
ability through CS-coated-Irinotecan (IRN)-loaded-PLGA
nanoparticles when compared with IRN solution.88
The Particle Containing Lipid Material
Group
The majority of orally administered drugs are absorbed
into the portal blood to reach the systemic circulation.
However, the lipophilic substances (log P>5) usually
reach the systemic circulation through the lymphatic
pathway.60 In addition, some papers have mentioned that
lipophilic substances and macromolecular substances with
large molecular weights can increase the lymphatic
absorption of drugs.89 Moreover, the permeability of lym­
phatic vessels to nanoparticles is significantly higher than
that of capillaries.90 In addition, absorption of drugs
through lymphatic vessels, due to its unique physiological
and anatomical structure, can prevent the first pass meta­
bolizing of liver.60,91 Therefore, through lymphatic absorp­
tion, the bioavailability of oral drugs can be significantly
increased.92 However, different lengths of fatty acid chains
have different absorption effects. The fatty acid chains
from c-14 to c-18 promote greater lymphatic
absorption.93 Khoo et al94 also found that long-chain tri­
glycerides promoted absorption more effectively than
medium-chain triglycerides. Moreover, certain classes of
phospholipids and surfactants used in the formulations of
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liposomes can suppress the P-gp efflux system, thereby
increased absorption of drugs.4
The Particle Containing Specific Ligands
Nanoparticle coated specific ligand has better intracellular
uptake trend. For instance, in order to study the effect of
folate functionalization on the extracellular transport of PTX,
a chemotherapy drug with poor oral bioavailability, Roger
et al95 modified PTX-PLGA nanoparticles with folate. Using
the Caco-2 monolayer as an in vitro model, confocal micro­
scopy showed that PTX loaded in PLGA nanoparticles
increased the apparent permeability in Caco-2 cells by
5-times compared with free PTX. Functionalization of nano­
particles with folic acid further increased the transport capa­
city (8-fold compared with free PTX).
As we all know, the pharmacokinetic process of cargos
in vivo is very complicated, and it is difficult to achieve
effective drug delivery via modifying nanoparticles with
only one kind of material. Therefore, nowadays, many studies
modify or prepare nanoparticles with different or even oppo­
site materials. Netsomboon et al36 mentioned that negatively
charged particles being capable of changing zeta-potential to
a positive value once having permeated the mucus and having
reached the epithelium might be a promising strategy.
Negatively charged and uncharged particles can easily move
through the mucus,32,96 whereas positively charged particles
show a comparatively much higher cell uptake via endocyto­
sis than negatively charged particles.97 A typical example was
that, after incubation with intestinal alkaline phosphatase, zeta
potential of nanoparticles exhibiting phosphotyrosine sub­
structures on their surface changed from negative to positive
due to cleavage of negative charges in the form of phosphate
residues.98 In addition, Shan et al66 reported a simple zwitter­
ions-based nanoparticle delivery platform, the dense and
hydrophilic coating of zwitterions endowed the nanoparticles
with excellent mucus penetrating ability and affinity with
epithelial cells, which significantly improved (4.5-fold) the
cellular uptake of nanoparticles, compared with PEGlated
nanoparticles. Wang et al11 developed a bilayer modification
on the surface of mesoporous silica nanoparticles (MSNs)
consisting of polyethylenimine-coated carbon dots (PCD)
for effective transepithelial absorption and PEG polymers
for improved mucus permeability, which enhanced the stabi­
lity in the physiological environment, altered cell uptake
mechanisms, and increased distribution in various intestinal
sections.
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The Effect of Shape for Oral
Bioavailability
In addition to surface properties and size of nanoparticles,
the shape of nanoparticles has a great influence on their
interaction with biological systems, including cellular
uptake, plasma circulation and organ distribution and so
on. However, understanding of how shape of nanoparticles
affects biological systems is far from complete. Nature
abounds in viruses and bacteria of various forms.99 It is
well known that bacterial forms have an evolutionary
advantage due to their interactions with surface mechan­
isms such as passive diffusion and active transport.100 In
Darwinian evolution, changes in bacterial or viral form
precede in function due to random mutations. There is
a strong case for natural selection of bacteria and viruses
with specific forms. In the future of medicine, nanoparti­
cles could also be shaped to suit their function.101
Most current NDDS used in laboratory-scale or clinical
trials are spherical due to ease of synthesis. However, nowa­
days, compounds in large numbers are being presented in
different forms of nanoparticles. For instance, Wang et al102
synthesized gold nanoparticles through one pot synthesis
with inorganic metal material Au. Different morphologies
could be obtained by changing the gold to calcium ion
concentration ratios during the synthesis. As the calcium
concentration decreased, the morphology changed from
hexagons to pentagons and to triangles. Similarly, Huang
et al19 fabricated different shaped MSNs (spheres, short rods
and long rods), via inorganic nonmetallic material, to study
the effect of MSNs on cellular behavior. In addition to
inorganic material, Yoo et al103 synthesized PLGA particles
with spherical and elliptical disk geometries and investigated
the effect of particle shape on rate of particle endocytosis
and their intracellular distribution in endothelial cells. This
section briefly summarizes and discusses the relationship
between different shapes of nanoparticles and common bio­
logical endpoints (eg, cell uptake, biological distribution).
Effects of Nanoparticle Morphology on
Cellular Uptake in vivo and in vitro
Cell membranes mainly permeate small and non-polar mole­
cules. Most nanoparticles are polar molecules that enter cells
via endocytosis rather than cell diffusion.104 Recently, particle
shape, an important physicochemical property of nanoparti­
cles, has gained great attention and been demonstrated experi­
mentally and theoretically to exert a great effect on cellular
uptake behaviors.105 Different morphological features of
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nanoparticles affect their endocytosis process. Though some chemistry, and particle composition, which play a dominant
studies have investigated the relationship between shape of role.
nanoparticles and uptake pathways, the revealed results have Endocytosis has two stages: adhesion and internali-
always been inconsistent (Table 3). For instance, it is well zation.109 The shape of nanoparticles has a significant impact
documented that rod-shaped nanoparticles have a lower capa­ on the cell adhesion of a wide variety of nanoparticles. Salatin
city of entering the cells in comparison with their spherical et al110 mentioned that the elongated nanoparticles showed
counterparts.106,107 The data of Wang et al107 also showed the higher efficiency in adhering to the cells rather than the sphe­
same results that sphere-shaped nanoparticles could enter rical nanoparticles. They explained that the curve shape of
mesenchymal stem cells at a faster rate in the initial 4 hours spherical particles allowed a limited number of their binding
than rod-shaped nanoparticles. A possible explanation for their sites to interact with target cell receptors while the elongated
results is that nanorods would seriously destroy the cytoske­ nanoparticles had higher surface area, which facilitated the
multivalent interaction of these particles with cell surface.
leton to cause the reorganization of the cytoskeleton, thereby
Similarly, Zhang et al109 mentioned that the prickly nanoparti­
prolonging the rate of cell internalization and resulting in slow
cles had a higher anchoring amount compared with the round
absorption. In contrast, nanospheres have less impact on the
nanoparticles. The results could be understood as originating
cytoskeleton and eventually get into cells faster.107 However,
from the contact surface area difference of the two types of
Gratton et al108 found that rod-shaped nanoparticles had the
nanoparticles with the plasma membrane. The paper of He and
highest internalization rates compared with spheres, cylinders,
Park111 suggested that a smaller diameter allowed the micro­
and cubes. The results of Banerjee et al6 demonstrated that the
sphere to adhere to cells faster and stronger. Therefore, we can
rod and disc-shaped nanoparticles were internalized 2-fold see that the larger surface area is likely to leadd to a stronger
higher than spherical nanoparticles. The possible reasons for adhesion to the cell. Since strong adhesion between the nano­
the uptake behaviors are governed by cell types, size, surface particles and the cells are required for cells to internalize the
nanoparticles, a larger the surface area implies a higher chance
internalized by cells.112
Table 3 The Different Internalization Pathways Corresponding
NDDS can be capable to enter live cells, often through
to Different Cells and the Main Shapes Associated with Them
several endocytic pathways, namely phagocytosis, macropi­
Cellular Cell Type Nanoparticle Ref nocytosis, clathrin-mediated endocytosis, and caveolin-
Mechanism Shape
mediated endocytosis.113 Phagocytosis only occurs in
Phagocytosis Macrophages Large ARs [116] specialized cells such as macrophages, monocytes, dendritic
Monocytes cells, natural killer cells, and neutrophils, which in turn form
intracellular phagosomes.114 Macropinocytosis is a process by
Dendritic cells
which extracellular fluid and its debris are internalized into
Natural killer a nonspecific manner within large, heterogeneous vesicles,
cells named macropinosomes.115 Clathrin-mediated endocytosis is
Neutrophils initiated by the interaction between ligands and specific recep­
tors. Following entry into the cell, a fraction of internalized
Macropinocytosis Endothelial cells [117]
guest matters would be recycled back to the cell exterior,
Epithelial cells
while the remaining fractions are transferred into lysosomes,
Clathrin-mediated Endothelial cells Sphere-shaped [118] resulting in the degradation of the sequestered cargo material
endocytosis particles by the lysosomal enzymes.116 The caveolae-mediated
Caveolin-mediated The capillary Large ARs [119] endocytosis pathway is characteristic by the evolution of
endocytosis endothelium caveolae-derivatives of the subdomains of sphingolipid and
cholesterol-rich cell membrane fractions, which mediates the
Type I epithelial
cells translocation to the Golgi apparatus, to endoplasmic reticulum
or entered into the endosomal pathway.117
Muscle cells
It has been revealed that the pathway of nanoparticles into
Fibroblasts cells can be regulated by shape. For instance, Hao et al105 used
Abbreviation: AR, aspect ratio. sphere-nanoparticles (NS), short-rod nanoparticles (NSR), and

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long-rod nanoparticles (NLR) to incubate with Hela cells.
Their results preliminarily demonstrated that NS particles
preferred to be internalized into cells via the clathrin-
mediated pathway, whereas the uptake is shifted to the caveo­
lae-mediated pathway for the particles with large aspect ratios
(ARs). In addition, Agarwal et al118 mentioned that, although
macropinocytosis was used by both epithelial and endothelial
cells, epithelial cells uniquely internalized these nanoparticles
using the caveolae-mediated pathway. Human umbilical vein
endothelial cells, on the other hand, used clathrin-mediated
uptake for all shapes and show a significantly higher uptake
efficiency compared with epithelial cells. Although less sig­
nificantly, it further confirmed that the effect of particle geo­
metry is cell type-specific. This shall be one of the reasons for
the inconsistency between different cells and dependence on
shape. Agarwal et al118 also proposed that when nanoparticle
surface properties and composition were kept constant, each
cell type could “sense” the nanoscale geometry (both shape
and size) and trigger unique uptake pathways and thus have
different shape-dependent internalization efficiencies.
Therefore, it is paramount to consider the main intercellular
pathways of different cells in exploring the effects of nano­
particle morphology on cellular uptake.
Sharma et al119 stretched three different volumes of
spherical PS particle, ranging from 0.5–3.6 µm in diameter
to form prolate or oblate ellipsoids which utilized the film-
stretching method and studied their attachment and inter­
nalization in RAW 264.7 murine macrophages. Regardless
of the volume, the order of particle adhesion to the mem­
brane surface was the oblong>oblate>sphere. However, the
order of internalization was the oblate>sphere>oblong.
Prior to this, Champion and Mitragotri120 also explored
the effect of nanoparticle morphology on macrophage
uptake in a similar approach. They found that regions of
higher curvature were associated with a larger degree of
wrapping or phagocytosis. As we all know, nanoparticles
enter in the system circulation after oral administration
where nanoparticles could be absorbed by immune cells in
the blood and various phagocytes in tissues. To avoid being
devoured by various immune cells or macrophages before
reaching the target tissue, this effect could be minimized by
controlling the local shape of the nanoparticles, thereby
increasing the bioavailability.103 In addition to macro­
phages, particle geometry has also been shown to have
a significant impact on the context of epithelial drug deliv­
ery. Banerjee et al6 investigated the uptake and transport of
smaller stretch nanoparticles in a triple-cell co-culture
model of the intestine. They found that rod-shaped and disc-
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Wang et al
shaped particles, stretched from 200 nm sphere-shaped
nanoparticles, were more readily absorbed and transported
by epithelial cells than spheres. Also, Huang et al19 fabri­
cated and functionalized different shaped MSNs (spheres,
short rods, and long rods) with fluorescein isothiocyanate
(FITC) and rhodamine B isothiocyanate (RITC) for ima­
ging and quantification of MSNs uptake. Then the ability of
different shaped MSNs to be transported into model A375
cells was compared. They found that the number of intra­
cellular particles varied with particle shape and exhibited
a strong dependence. Compared with spherical and short
rod-shaped nanoparticles, long rod-shaped nanoparticles
were easier to internalize. The authors suggested that one
possible explanation was the curvature of different shapes.
The area of contact between rod nanoparticles and the cell
membrane was larger than that of spherical nanoparticles
because the longitudinal axis of rod nanoparticles interacted
with the cell membrane.
Although the main internalization pathways of
nanoparticles change with different cells, it could be
speculated from the above studies that the curvature of
nanoparticles and the area of contact with cells play
important roles.
Another study said that the morphology dependence of
cell uptake varied with the size of nanoparticles.101 They
believed that larger particles had a general pattern of
morphological dependence, while smaller nanoparticles
did not have morphological dependence in cellular uptake
because small particles tended to change the surface prop­
erties of nanoparticles. In addition to nanoparticle size, the
nanoparticle materials mentioned above also had
a significant impact on the shape dependence of cell
uptake. Using Jet and Flash Imprint Lithography (J-FIL)
for top down fabrication of monodisperse, Agarwal et al118
fabricated PEG-based discoidal and cuboidal rod-shaped
nanoparticles. Particles were administered to cells in cul­
ture at equal total fluorescence intensity. They found that
between discoidal and rod-shaped nanoparticles of similar
volume, nanodiscs were more efficiently internalized at
any time points. Nevertheless, Barua et al121 reported
that for nonspecific hydrophobic PS particles, nanorods
and nanodiscs possessed similar uptake in epithelial breast
cancer cells. These differences could highlight the effect of
nanoparticle size and modification as well as cell types
evaluated and emphasize the importance of material and
size composition in understanding nanoparticle-mediated
intracellular delivery.
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Effects of Nanoparticle Morphology on
GI Transit
Geometry not only affects cellular uptake, but also influences
transport across the physiological barriers. Nanorods and
nanospheres were labeled using fluorescence resonance
energy transfer (FRET) molecules to track the in vivo fate
of intact nanoparticles accurately.122 Li et al122 found that
nanorods possessed significantly longer retention time in the
GI tract compared with nanospheres. Furthermore, nanorods
exhibited a stronger ability of penetration into space of villi
than nanospheres, which was the main reason of longer
retention time. In addition, mesenteric lymph transported
1.75% nanorods within 10 hours, which was more than
nanospheres (0.98%). It indicated the nanoparticles shape
could affect the movement route or rate. Yu et al123 found
that mesoporous silica rods (80×240 nm) as well as calcium
phosphate rods have also been shown to penetrate deeper into
the mucosal tissue of the GI tract ex vivo compared with
spheres (80 and 140 nm). They guessed that this effect
originated from their rotational diffusion combined with
shear flows and the mesh-like network of mucus enabling
deep penetration of the viscoelastic layer. Combined, these
two studies suggested anisotropic and rod-like particles were
far superior to targeting the epithelium of the GI tract than
their spherical equivalents.
Conclusion and Prospective
The physicochemical properties of nanoparticles can signif­
icantly affect oral bioavailability of drugs. However, oral
delivery of drugs is a complex process. And variation in one
area alone of nanoparticles cannot fully improve the oral
bioavailability of drugs. Therefore, it is important to under­
stand the role of nanoparticles in the oral delivery. Finally,
efforts should focus not only on the laboratory synthesis/
functionalization, but also on the selection of appropriate
materials for the preparation of nanoparticles according to
clinical needs, so as to increase the oral absorption and
improve the oral bioavailability of drugs. Here, we have
preliminarily covered the different roles played by different
properties of nanoparticles in oral drug delivery to provide
corresponding assistance to researchers in this field.
Acknowledgments
This study was supported by the basic research fund of the
Science and Technology Department of Sichuan Province
(No. 2020YJ0336, 2020YJ0373), the Joint Fund of Luzhou
City and Southwest Medical University [No.2017LZXNYD-
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T02, 2019LZXNYDZ07], the Science and Technology Fund
of Luzhou City (No. 2019-SYF-35), and Science and
Technology Innovation Team from Jiucheng Science and
Technology Talent Cultivation Plan in Luzhou City (2019-1).
Disclosure
Yuanyuan Wang reports grants from the Science and
Technology Fund for Distinguished Young Scholars of
Sichuan Province and Basic Research, the Joint Fund of
Luzhou City and Southwest Medical University, the
Science and Technology Fund of Luzhou City, Science and
Technology Innovation Team from Jiucheng Science and
Technology Talent Cultivation Plan in Luzhou City, the
Scientific Research Foundation of the Education
Department of Sichuan Province, and a research grant from
Traditional Chinese Medicine Administration in Sichuan
Province, during the conduct of the study. The authors report
no other potential conflicts of interest in this work.
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